tert-butyl 4-fluorobenzoate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of t-butyl 4-fluorobenzoate (2.17 g, 11.0 mmol) and (R)-(+)-3-pyrrolidinol (1.00 g, 11.5 mmol) in DMSO (8 mL) was added potassium carbonate (1.53 g, 11.0 mmol). The mixture was stirred at 130° C. for 18 h and poured into stirring water (100 mL) while still hot. The resulting beige precipitate was collected by filtration and dried at 120° C. for 1.5 h to afford the title compound (2.64 g, 91% yield). 1H NMR (Acetone-d6) δ (ppm): 7.78 (d, J=9.0 Hz, 2H), 6.54 (d, J=8.8 Hz, 2H), 4.58 (bs, 1H), 4.15 (bs, 1H), 3.55 (dd, J=10.36, 4.7 Hz, 1H), 3.49 (t, J=6.8 Hz, 1H), 3.42 (td, J=9.2, 2.3 Hz, 1H), 3.28 (d, J=10.8 Hz, 1H), 2.21-2.10 (m, 1H), 2.09-2.03 (m, 1H), 1.56 (s, 9H). m/z: 520.3 (MH+). poured The resulting beige precipitate was collected by filtration dried at 120° C. for 1.5 h

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: tert-Butyl 4-fluorobenzoate 185 (0.502 g, 2.55 mmol) and 2-(piperidin-1-yl)ethanamine 186 (1.46 mL, 10.21 mmol) were stirred neat at 120° C. overnight then diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate (1×), brine (1×), dried over magnesium sulfate and evaporated to give 187 (0.501 g, 64%). 1H NMR: (DMSO) δ (ppm): 400 MHz, (DMSO) d (ppm): 7.59 (d, J=8.8 Hz, 2H), 6.55 (d, J=8.8 Hz, 2H), 6.24 (t, J=5.1 Hz, 1H), 4.11 (m, 2H), 3.21 to 3.13 (m, 6H), 2.44 (t, J=7.1 Hz, 2H), 2.37 (m, 2H), 1.49 (s, 9H), 1.47 to 1.38 (m, 2H). MS: 304.22 (calc), 249.1 (M-tBu). washed with saturated aqueous sodium bicarbonate (1×), brine (1×) dried over magnesium sulfate evaporated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: tert-Butyl 4-fluorobenzoate 185 (0.502 g, 2.55 mmol) and 2-(piperidin-1-yl)ethanamine 186 (1.46 mL, 10.21 mmol) were stirred neat at 120° C. overnight then diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate (1×), brine (1×), dried over magnesium sulfate and evaporated to give 187 (0.501 g, 64%). 1H NMR: (DMSO) δ (ppm): 400 MHz, (DMSO) d (ppm): 7.59 (d, J=8.8 Hz, 2H), 6.55 (d, J=8.8 Hz, 2H), 6.24 (t, J=5.1 Hz, 1H), 4.11 (m, 2H), 3.21 to 3.13 (m, 6H), 2.44 (t, J=7.1 Hz, 2H), 2.37 (m, 2H), 1.49 (s, 9H), 1.47 to 1.38 (m, 2H). MS: 304.22 (calc), 249.1 (M-tBu). washed with saturated aqueous sodium bicarbonate (1×), brine (1×) dried over magnesium sulfate evaporated

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: tert-Butyl p-fluorobenzoate (750 mg, 3.93 mmol, 1 equiv) was dissolved in ethylenediamine (4 mL), and heated to 120° C. for 24 h. All solvent was evaporated, and then the residue was dry-loaded onto silica gel and purified by flash column chromatography (eluent CH2Cl2/MeOH/NH4OH, 92:7:1) to furnish tert-butyl 4-(2-amino-ethylamino)-benzoate as a white powder (891 mg, 96%): δH (400 MHz, CD2Cl2) 1.59 (s, 9H, CO2(CH3)3), 2.98 (t, J=5.8 Hz, 2H, H2NCH2CH2NH), 3.23 (q, J=5.8 Hz, 2H, H2NCH2CH2NH), 4.67 (br, 1H, H2NCH2CH2NH), 6.62 (d, J=8.6 Hz, 2H, 2 CH (Ar)), 7.81 (d, J=8.6 Hz, 2H, 2 CH (Ar)); δC (125 MHz, CD2Cl2) 28.9, 41.7, 46.6, 80.3, 112.1, 120.9, 131.9, 152.9, 166.7; HRMS (EI+) m/z calcd for [C13H20N2O2] 236.1525. found 236.1527. tert-Butyl 4-(2-amino-ethylamino)-benzoate (700 mg, 3.03 mmol, 1 equiv) was then sulfonylated with 1-methyl-1H-imidazole-4-sulfonyl chloride. The appropriate sulfonyl chloride (1.2 equiv) was added to a solution of the amine (1 equiv) and DIPEA (2 equiv) in anhydrous CH3CN (0.1 M) at 0° C. The reaction was warmed to room temperature and stirred for 16 h, at which time the solvent was evaporated. The residue was re-dissolved in CH2Cl2, washed with 5% NaHCO3, water, brine, dried (Na2SO4), filtered and concentrated. The crude material was dry-loaded onto silica gel, and then purified by flash column chromatography (eluent CH2Cl2/MeOH/NH4OH, 192:7:1) to give tert-butyl 4-[2-(1-methyl-1H-imidazole-4-sulfonylamino)-ethylamino]-benzoate as a white powder (1.04 g, 90%): δH (500 MHz, CDCl3) 1.56 (s, 9H, CO2(CH3)3), 3.17 (m, 2H, SO2NHCH2CH2NH), 3.28 (m, 2H, SO2NHCH2CH2NH), 3.67 (s, 3H, CH3 (Im)), 6.51 (d, J=8.5 Hz, 2H, 2 CH (Ar)), 7.46 (s, 1H, CH (Im)), 7.51 (s, 1H, CH (Im)), 7.75 (d, J=8.5 Hz, 2H, 2 CH (Ar)); δC (125 MHz, MeOH-d4) 28.7, 34.6, 42.4, 43.1, 80.8, 111.9, 120.5, 125.2, 131.8, 140.1, 140.3, 152.4, 167.4; HRMS (ES+) calcd for [C17H24N4O4S+H] 381.1597. found 381.1573. tert-Butyl 4-[2-(1-methyl-1H-imidazole-4-sulfonylamino)-ethylamino]-benzoate (610 mg, 1.63 mmol, 1 equiv) was then chemoselectively benzylated on the sulfonamide NH with benzyl bromide. To a solution of the sulfonamide (1 equiv) and Cs2CO3 (2 equiv) in DMF (0.1 M) at 0° C. was added the appropriate alkyl bromide or chloride (1.1 equiv). The resulting mixture was stirred at room temperature overnight. The reaction was diluted with water, then extracted into EtOAc (×3). The combined EtOAc extractions were washed with 5% NaHCO3 (×3), brine, dried (Na2SO4), filtered and concentrated. The crude material was then flash chromatographed over silica gel to furnish tert-butyl 4-{2-[benzyl-(1-methyl-1H-imidazole-4-sulfonyl)-amino]-ethylamino}-benzoate as a white solid (703 mg, 92%): δH (400 MHz, CDCl3) 1.52 (s, 9H, CO2(CH3)3), 3.13 (t, J=6.2 Hz, 2H, (Bn)NCH2CH2NH), 3.43 (t, J=6.2 Hz, 2H, (Bn)NCH2CH2NH), 3.68 (s, 3H, CH3 (Im)), 4.32 (s, 2H, CH2Ph), 6.30 (d, J=8.8 Hz, 2H, 2 CH (Ar)), 7.23-7.30 (m, 5H, 5 CH (Ph)), 7.42 (s, 1H, CH (Im)), 7.49 (s, 1H, CH (Im)), 7.70 (d, J=8.8 Hz, 2H, 2 CH (Ar)); δC (500 MHz, CDCl3) 28.1, 33.9, 41.6, 46.6, 52.6, 79.6, 111.1, 119.9, 124.4, 127.9, 128.3, 128.6, 131.1, 136.0, 139.0, 139.8, 151.1, 166.1; HRMS (ES+) calcd for [C24H30N4O4S+H] 471.2066. found 471.2053. tert-Butyl 4-{2-[benzyl-(1-methyl-1H-imidazole-4-sulfonyl)-amino]-ethylamino}-benzoate (220 mg, 0.473 mmol, 1 equiv) was alkylated on the aniline NH with 5-chloromethyl-1-methyl-1H-imidazole.HCl. The secondary aniline (1 equiv) was dissolved in DMF (0.07 M), then the reaction was cooled to 0° C. After 15 min, NaH (3 eq.) was added in one portion. After a further 15 min, 5-chloromethyl-1-methyl-1H-imidazole.HCl (1.1 eq) was added. The reaction was allowed to stir at 0° C. from 2-3 h, when TLC indicated the reaction was complete or had stalled. Upon quenching the reaction with brine (approximately 1 mL), the reaction was diluted with water and extracted with EtOAc (×3). The EtOAc extractions were combined, and washed with 5% NaHCO3 (×3), brine, dried (Na2SO4), filtered and concentrated. The crude material was flash chromatographed over silica gel (eluent CH2Cl2/MeOH/NH4OH, 192:7:1) to afford the title compound 10 as a colourless foam (200 mg, 76%): δH (500 MHz, CDCl3) 1.53 (s, 9H, C(CH3)3), 3.09-3.15 (m, 2H, CH2CH2NSO2), 3.29-3.34 (m, 2H, CH2CH2NSO2), 3.43 (s, 3H, CH3), 3.73 (s, 3H, CH3), 4.26 (s, 2H, CH2Ph), 4.30 (s, 2H, CH2Im), 6.35 (d, J=9.0 Hz, 2H, 2 CH (Ar)), 6.69 (s, 1H, CH (Im)), 7.31-7.37 (m, 5H, 5 CH (Ph)), 7.39 (s, 1H, CH (Im)), 7.42 (s, 1H, CH (Im)), 7.46 (s, 1H, CH (Im)), 7.68 (d, J=9.0 Hz, 2H, 2 CH (Ar)); δC (125 MHz, CDCl3) 28.2, 31.6, 33.9, 44.1, 45.0, 49.7, 54.3, 79.8, 111.0, 120.0, 124.4, 127.5, 128.1, 128.6, 128.7, 128.9, 131.1, 136.2, 138.5, 139.0, 139.1, 150.3, 165.8; HRMS calcd for [C29H36N6O4S+H] 565.2597. found 565.2576; HPLC (I) tR=12.53 min (100%), (II) tR=18.77 min (100%). All solvent was evaporated purified by flash column chromatography (eluent CH2Cl2/MeOH/NH4OH, 92:7:1)

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: tert-Butyl p-fluorobenzoate (750 mg, 3.93 mmol, 1 equiv) was dissolved in ethylenediamine (4 mL), and heated to 120° C. for 24 h. All solvent was evaporated, and then the residue was dry-loaded onto silica gel and purified by flash column chromatography (eluent CH2Cl2/MeOH/NH4OH, 92:7:1) to furnish tert-butyl 4-(2-amino-ethylamino)-benzoate as a white powder (891 mg, 96%): δH (400 MHz, CD2Cl2) 1.59 (s, 9H, CO2(CH3)3), 2.98 (t, J=5.8 Hz, 2H, H2NCH2CH2NH), 3.23 (q, J=5.8 Hz, 2H, H2NCH2CH2NH), 4.67 (br, 1H, H2NCH2CH2NH), 6.62 (d, J=8.6 Hz, 2H, 2 CH (Ar)), 7.81 (d, J=8.6 Hz, 2H, 2 CH (Ar)); δC (125 MHz, CD2Cl2) 28.9, 41.7, 46.6, 80.3, 112.1, 120.9, 131.9, 152.9, 166.7; HRMS (EI+) m/z calcd for [C13H20N2O2] 236.1525. found 236.1527. tert-Butyl 4-(2-amino-ethylamino)-benzoate (700 mg, 3.03 mmol, 1 equiv) was then sulfonylated with 1-methyl-1H-imidazole-4-sulfonyl chloride. The appropriate sulfonyl chloride (1.2 equiv) was added to a solution of the amine (1 equiv) and DIPEA (2 equiv) in anhydrous CH3CN (0.1 M) at 0° C. The reaction was warmed to room temperature and stirred for 16 h, at which time the solvent was evaporated. The residue was re-dissolved in CH2Cl2, washed with 5% NaHCO3, water, brine, dried (Na2SO4), filtered and concentrated. The crude material was dry-loaded onto silica gel, and then purified by flash column chromatography (eluent CH2Cl2/MeOH/NH4OH, 192:7:1) to give tert-butyl 4-[2-(1-methyl-1H-imidazole-4-sulfonylamino)-ethylamino]-benzoate as a white powder (1.04 g, 90%): δH (500 MHz, CDCl3) 1.56 (s, 9H, CO2(CH3)3), 3.17 (m, 2H, SO2NHCH2CH2NH), 3.28 (m, 2H, SO2NHCH2CH2NH), 3.67 (s, 3H, CH3 (Im)), 6.51 (d, J=8.5 Hz, 2H, 2 CH (Ar)), 7.46 (s, 1H, CH (Im)), 7.51 (s, 1H, CH (Im)), 7.75 (d, J=8.5 Hz, 2H, 2 CH (Ar)); δC (125 MHz, MeOH-d4) 28.7, 34.6, 42.4, 43.1, 80.8, 111.9, 120.5, 125.2, 131.8, 140.1, 140.3, 152.4, 167.4; HRMS (ES+) calcd for [C17H24N4O4S+H] 381.1597. found 381.1573. tert-Butyl 4-[2-(1-methyl-1H-imidazole-4-sulfonylamino)-ethylamino]-benzoate (610 mg, 1.63 mmol, 1 equiv) was then chemoselectively benzylated on the sulfonamide NH with benzyl bromide. To a solution of the sulfonamide (1 equiv) and Cs2CO3 (2 equiv) in DMF (0.1 M) at 0° C. was added the appropriate alkyl bromide or chloride (1.1 equiv). The resulting mixture was stirred at room temperature overnight. The reaction was diluted with water, then extracted into EtOAc (×3). The combined EtOAc extractions were washed with 5% NaHCO3 (×3), brine, dried (Na2SO4), filtered and concentrated. The crude material was then flash chromatographed over silica gel to furnish tert-butyl 4-{2-[benzyl-(1-methyl-1H-imidazole-4-sulfonyl)-amino]-ethylamino}-benzoate as a white solid (703 mg, 92%): δH (400 MHz, CDCl3) 1.52 (s, 9H, CO2(CH3)3), 3.13 (t, J=6.2 Hz, 2H, (Bn)NCH2CH2NH), 3.43 (t, J=6.2 Hz, 2H, (Bn)NCH2CH2NH), 3.68 (s, 3H, CH3 (Im)), 4.32 (s, 2H, CH2Ph), 6.30 (d, J=8.8 Hz, 2H, 2 CH (Ar)), 7.23-7.30 (m, 5H, 5 CH (Ph)), 7.42 (s, 1H, CH (Im)), 7.49 (s, 1H, CH (Im)), 7.70 (d, J=8.8 Hz, 2H, 2 CH (Ar)); δC (500 MHz, CDCl3) 28.1, 33.9, 41.6, 46.6, 52.6, 79.6, 111.1, 119.9, 124.4, 127.9, 128.3, 128.6, 131.1, 136.0, 139.0, 139.8, 151.1, 166.1; HRMS (ES+) calcd for [C24H30N4O4S+H] 471.2066. found 471.2053. tert-Butyl 4-{2-[benzyl-(1-methyl-1H-imidazole-4-sulfonyl)-amino]-ethylamino}-benzoate (220 mg, 0.473 mmol, 1 equiv) was alkylated on the aniline NH with 5-chloromethyl-1-methyl-1H-imidazole.HCl. The secondary aniline (1 equiv) was dissolved in DMF (0.07 M), then the reaction was cooled to 0° C. After 15 min, NaH (3 eq.) was added in one portion. After a further 15 min, 5-chloromethyl-1-methyl-1H-imidazole.HCl (1.1 eq) was added. The reaction was allowed to stir at 0° C. from 2-3 h, when TLC indicated the reaction was complete or had stalled. Upon quenching the reaction with brine (approximately 1 mL), the reaction was diluted with water and extracted with EtOAc (×3). The EtOAc extractions were combined, and washed with 5% NaHCO3 (×3), brine, dried (Na2SO4), filtered and concentrated. The crude material was flash chromatographed over silica gel (eluent CH2Cl2/MeOH/NH4OH, 192:7:1) to afford the title compound 10 as a colourless foam (200 mg, 76%): δH (500 MHz, CDCl3) 1.53 (s, 9H, C(CH3)3), 3.09-3.15 (m, 2H, CH2CH2NSO2), 3.29-3.34 (m, 2H, CH2CH2NSO2), 3.43 (s, 3H, CH3), 3.73 (s, 3H, CH3), 4.26 (s, 2H, CH2Ph), 4.30 (s, 2H, CH2Im), 6.35 (d, J=9.0 Hz, 2H, 2 CH (Ar)), 6.69 (s, 1H, CH (Im)), 7.31-7.37 (m, 5H, 5 CH (Ph)), 7.39 (s, 1H, CH (Im)), 7.42 (s, 1H, CH (Im)), 7.46 (s, 1H, CH (Im)), 7.68 (d, J=9.0 Hz, 2H, 2 CH (Ar)); δC (125 MHz, CDCl3) 28.2, 31.6, 33.9, 44.1, 45.0, 49.7, 54.3, 79.8, 111.0, 120.0, 124.4, 127.5, 128.1, 128.6, 128.7, 128.9, 131.1, 136.2, 138.5, 139.0, 139.1, 150.3, 165.8; HRMS calcd for [C29H36N6O4S+H] 565.2597. found 565.2576; HPLC (I) tR=12.53 min (100%), (II) tR=18.77 min (100%). All solvent was evaporated purified by flash column chromatography (eluent CH2Cl2/MeOH/NH4OH, 92:7:1)

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Tyramine (700 mg, 5.1 mmol) was added to a magnetically stirred suspension of potassium hydride (35 wt. percent dispersion in oil; 876 mg, 7.64 mmol) in DMF (20 mL) at 25° C. After effervescence stopped, tert-butyl 4-fluorobenzoate (1.0 g, 5.1 mmol) was added. After stirring at 25° C. for 64 hours, the reaction was warmed to 60° C. After 48 h, the reaction was poured into brine and extracted with hexanes (3×25 mL) and ethyl acetate (2×25 mL). Organic layers washed separately with aqueous 2 N NaOH, dried (Na2SO4), then pooled, evaporated and purified by silica gel chromatography (CH2Cl2:MeOH/2:1) to provide 0.98 g of clear oil. the reaction was warmed to 60° C After 48 h extracted with hexanes (3×25 mL) and ethyl acetate (2×25 mL) Organic layers washed separately with aqueous 2 N NaOH dried (Na2SO4) evaporated purified by silica gel chromatography (CH2Cl2:MeOH/2:1)

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Tyramine (700 mg, 5.1 mmol) was added to a magnetically stirred suspension of potassium hydride (35 wt. percent dispersion in oil; 876 mg, 7.64 mmol) in DMF (20 mL) at 25° C. After effervescence stopped, tert-butyl 4-fluorobenzoate (1.0 g, 5.1 mmol) was added. After stirring at 25° C. for 64 hours, the reaction was warmed to 60° C. After 48 h, the reaction was poured into brine and extracted with hexanes (3×25 mL) and ethyl acetate (2×25 mL). Organic layers washed separately with aqueous 2 N NaOH, dried (Na2SO4), then pooled, evaporated and purified by silica gel chromatography (CH2Cl2:MeOH/2:1) to provide 0.98 g of clear oil. the reaction was warmed to 60° C After 48 h extracted with hexanes (3×25 mL) and ethyl acetate (2×25 mL) Organic layers washed separately with aqueous 2 N NaOH dried (Na2SO4) evaporated purified by silica gel chromatography (CH2Cl2:MeOH/2:1)